Atopic dermatitis is one of incurable diseases and mainly divided into two paradigms, depending on their causes for the diseases. One is a inside-outside paradigm that atopic diseases are considered to be common allergic diseases and atopic dermatitis is caused by immunological disorders. The other is an outside-inside paradigm that a variety of allergic factors are easily penetrated into the skin owing to the dysfunction of skin barrier and therefore develop into the atopic dermatitis. According to the outside-inside paradigm, it is described that, since a barrier function against the skin penetration becomes weak with decreasing content of ceramide that is one main component in intercellular lipid of skin corneum, the skin develops into the atopic diseases due to the easy induction of xeroderma and the easy penetration of microorganism or allergens from outside environments. Accordingly, there has been an attempt to manage atopic diseases by supplementing lipid components such as ceramide in the corneum, or recovering its lamellar structure including the lipid components, and the present inventors have developed and merchandised analogous ceramide that is able to show an ability that is similar to the ceramide in vivo.
In addition to the barrier function recovery by the supplement of these ceramide formulations, it is, however, important to recover the damaged skin barrier functions (epidermal hyperplasia) and supplement barrier functions under the control of the differentiation of keratinocytes. In the case of the atopic dermatitis, the skin barrier functions are more seriously damaged by the epidermal proliferation, compared to the normal skin. Also, differentiation-associated proteins such as involucrin, loricrin, filaggrin and the like are expressed in a reduced amount or in abnormal patterns due to the deteriorated differentiation functions of the keratinocytes. Therefore, it is possible to improve atopic dermatitis through the improvement of the skin barrier functions using methods for suppressing epidermal proliferation caused by the barrier damages or facilitating normal differentiations of keratinocytes.
However, since it is difficult to treat atopic diseases by means of the recovery of the skin barrier function and the normal homeostasis of the skin, there has also been an attempt to develop a therapeutic agent for treating atopic dermatitis in aspect of its immunological pathogenesis. A variety of dermatitis including atopic dermatitis are referred to as inflammatory responses that are caused by the abnormal immune system in the skin, and therefore there have been various attempts to treat this dermatitis. Representative methods includes a method using a T cell inhibiting agent, a method using an anti-TNFα agent (malignant tumor necrosis factor-αagent), etc.
As a representative immunosuppressive agent, the T cell inhibiting agent includes calcineurin inhibiting agents such as cyclosporin, tacrolimus and pimecrolimus, and mycophenolate. The calcineurin inhibiting agents acts to suppress expression of interleukin-2(IL-2) and IL-2 receptor genes through the suppression of nuclear factor of activated T cells (NF-AT). Cyclosporin is not used as a topical agent since the cyclosporin shows a potent immunosuppressive effects when it is orally administered, but it does not penetrated into the skin when it is applied to the skin. On the contrary, tacrolimus and pimecrolimus have been approved for their use since they show a potent immunosuppressive effect when they are applied to the skin. However, when the tacrolimus and pimecrolimus are applied to the skin, they develop into various side effects such as the increase in infection rates due to the weakened immune system, as well as side effects such as burning, pruritus, erythema, irritation, edema, urticaria, etc. As another T cell inhibiting agent, the mycophenolate is an inhibiting agent of inhibiting purine biosynthesis in the de novo pathway that suppresses functions of T cells and B cells. It has been known that the mycophenolate is effective to treat atopic dermatitis when it is orally administered, but its effects have not been verified when it is applied to the skin.
TNFα is a proinflammatory cytokine that plays an important role in dermatitis. A representative anti-TNFα agent includes infliximab and etanercept. The infliximab and etanercept have been originally developed as a therapeutic agent for treating arthritis, and approved as the therapeutic agent for treating arthritis from FDA. In the clinical test, it has, however, been reported that the infliximab and etanercept are effective to treat various dermatitis including chronic dermatitis such as psoriasis, Behcet's syndrome, etc. It has been known that the infliximab and etanercept have various side effects in the digestive system and the respiratory system, as well as side effects such as headache. Also, the infliximab and etanercept are injected as antibody against the TNFα in protein formulations, but their effects are not proven when they are applied to the skin.
Although the above-mentioned immunosuppressive agents have various effects, they are used to treat severe dermatitis since they have their various side effects.
Accordingly, the therapeutic agents for treating atopic dermatitis, which do not have side effects and skin irritations and show their anti-inflammatory effects when they are applied to the skin, may be very useful as in the therapeutic agent for treating atopic dermatitis according to the present invention.